Neoadjuvant Gemcitabine and Cisplatin in Combination With Perioperative Pembrolizumab Versus Upfront Surgery for Patients With Primary Resectable and Borderline Resectable Perihilar and Distal Cholangiocarcinoma (NEODISCO)

Neoadjuvant Gemcitabine and Cisplatin in Combination With Perioperative Pembrolizumab Versus Upfront Surgery for Patients With Primary Resectable and Borderline Resectable Perihilar and Distal Cholangiocarcinoma (NEODISCO): A Multicentre Phase 2B/3 Randomized Controlled Trial

Extrahepatic cholangiocarcinoma (eCCA) is a rare and aggressive cancer with poor prognosis. ECCA can be further subcategorised in perihilar and distal cholangiocarcinoma (pCCA and dCCA). Surgical resection is the only potential cure, but only one-third of patients are eligible. Even among those deemed resectable, a significant portion (≈30%) experience disease progression before surgery, while another 30% are found unresectable during exploration. High recurrence rates and postoperative complications further limit survival, with 5-year overall survival ranging from 13% (R1 resection) to 40% (R0 resection). Given the long preoperative work-up period and lack of treatment during this phase, a neoadjuvant approach may improve outcomes by increasing R0 resections, reducing recurrence, and optimizing patient selection.

This multicenter, randomized phase 2B/3 trial aims to assess whether neoadjuvant gemcitabine and cisplatin plus perioperative pembrolizumab improves event-free survival in patients with resectable and borderline resectable pCCA and dCCA.

Study Overview

• Status: Not yet recruiting
• Conditions: Extrahepatic Cholangiocarcinoma; Distal Cholangiocarcinoma; Perihilar Cholangiocarcinoma; Resectable; Borderline Resectable
• Intervention / Treatment: Drug: Pembrolizumab; Drug: Gemcitabine, Cisplatin

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Johanna Wilmink, MD, PhD; Phone Number: +31-20-4444321; Email: trialmedonc@amsterdamumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam University Medical Center
    • Contact: Britte ten Haaft, MD; Phone Number: +31-20-4444321; Email: b.tenhaaft@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed resectable or borderline resectable pCCA and dCCA. These are all the patients considered candidates for upfront surgical exploration, with intent to resect, as confirmed by local MDT and the study expert panel also taking into consideration endoscopic and radiological findings. In cases where drainage is not required, patients with a disease highly suspicious for extrahepatic cholangiocarcinoma, as determined by the expert MDT, may be included without histological proof to prevent unnecessary post-ERCP complications.
• Successful drainage, in case of clinical significant bile duct obstruction.
• MidCCA inclusion in the NEODISCO-trial will be permitted and will be included according to the proposed type of resection.
• Male/female participants who are at least 18 years of age on the day of signing informed consent.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.

Exclusion Criteria:

• Upfront "clearly" unresectable pCCA: circumferential unreconstructable vascular involvement of the FLR and/or insufficient FLR for potential radical resection. Insufficient FLR is defined as <30% residual volume or a function <2.7 min/m2. Patients considered borderline resectable but, by the discretion of the MDT, not a candidate for upfront exploration/resection, are considered ineligible for NEODISCO.
• Upfront clearly unresectable dCCA (following DPCG criteria).
• Patients with proven N2 lymph nodes (according to the AJCC 8th edition).
• PCCA eligible for liver transplantation.
• Intrahepatic cholangiocarcinoma with hilar involvement.
• Cancer suspicious for ampullary carcinoma (for instance involvement of papilla during endoscopy).
• Local recurrence following prior resection of eCCA (patients who develop local recurrence during the study are however not excluded).
• Patients with underlying liver diseases: PSC, untreated hepatitis, cirrhosis child-Pugh B, C.
• Previous malignancy unless no evidence of disease, or diagnosed more than 3 years before diagnosis of eCCA, or with a life expectancy of more than 5 years from date of inclusion.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Neoadjuvant gemcitabine plus cisplatin in combination with perioperative pembrolizumab (Intervention)	Drug: Pembrolizumab; Patients will initiate with 2 sets of 3 cycles of neoadjuvant gemcitabine and cisplatin in combination with perioperative pembrolizumab (up to total of 1 year immunotherapy treatment); Drug: Gemcitabine, Cisplatin; Patients will initiate with 2 sets of 3 cycles of neoadjuvant gemcitabine and cisplatin in combination with perioperative pembrolizumab (up to total of 1 year immunotherapy treatment)
No Intervention: Arm B; Upfront surgery (Standard of care)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event Free Survival	An event is defined as the time from randomization to any progression of disease leading to unresectability, progression or recurrence of disease after surgery (all based on RECIST or pathology) or death from any cause.	18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Most important secondary endpoint: median OS defined as the time from randomization to death due to any cause. 2-, 3- and 5-years OS will also be reported.	Median, 2-, 3-, 5- years OS

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: University Medical Center Groningen; Maastricht University Medical Center; UMC Utrecht; Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): May 5, 2025
• Primary Completion (Estimated): November 6, 2028
• Study Completion (Estimated): November 6, 2028

Study Registration Dates

• First Submitted: February 25, 2025
• First Submitted That Met QC Criteria: April 3, 2025
• First Posted (Actual): April 11, 2025

Study Record Updates

• Last Update Posted (Actual): April 11, 2025
• Last Update Submitted That Met QC Criteria: April 3, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Resectable; Extrahepatic cholangiocarcinoma; Borderline resectable; Perihilar Cholangiocarcinoma; Distal Cholangiocarcinoma
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Carcinoma; Cholangiocarcinoma; Klatskin Tumor; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Gemcitabine; Pembrolizumab
• Other Study ID Numbers: 2024-516898-72-00; R-000724 (Other Grant/Funding Number: Merck Sharp & Dohme)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No